Treatment of migraine

ABSTRACT

A method for treating migraine in non-epileptic subjects which involves administering to subjects an effective amount of a pharmaceutical composition comprising a sulfamate of the following formula:

[0001] This application is a continuation application of U.S. Ser. No.09/436,003, filed Nov. 9, 1999, which claims the benefit of U.S. Ser.No. 08/542,950, filed on Oct. 13, 1995 (now U.S. Pat. No. 5,998,380).The contents of U.S. Ser. No. 09/436,003 and U.S. Ser. No. 08/542,950are incorporated here by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] This invention relates to treatment of migraine syndrome.

DESCRIPTION OF RELATED ART

[0003] A working definition of migraine is a benign recurring headacheand/or neurologic dysfunction, more common in women than men.

[0004] Classic migraine (migraine with aura) refers to the syndrome of asevere, throbbing headache which often is proceeded by sensory, motor orvisual symptoms, referred to as an “aura.” Common migraine (migrainewithout aura) denotes a headache without the aura. Common migraine isthe most frequent headache type reported by patients.

[0005] Many drugs are now available for prophylactic treatment ofmigraine. They must be taken daily. The major drugs for prophylaxis arepropanolol, amitriptyline, valproate, verapamil, phenelzine, andmethysergide. Use of methysergide carries with it the danger ofretroperitoneal fibrosis. Aspirin-like drugs, including aspirin,naproxen, ibuprofen, mefenamic acid, flufenamic acid, and tolfenamicacid are in use as prophylactic agents. The high dosage of thesecompounds required for effectiveness is a drawback. It has beenestimated that the probability of success with any one of the availableprophylactic antimigraine drugs is about 60 to 75% (Harrison'sPrinciples of Internal Medicine, eds. Isselbacher et al., McGraw-Hill,Inc., New York, 1994, p. 69). Accordingly, development or identificationof drugs for prophylactic treatment of migraine is an area of continuingmedical need.

SUMMARY OF THE INVENTION

[0006] The invention features administering sulfamates of the followingformula (I):

[0007] wherein X is O or CH₂ and R₁, R₂, R₃, R₄, and R₅ are ashereinafter defined, to prophylactically control migraines innon-epileptic subjects. The most preferred compound is topiramate,described below. Topiramate has been used to treat epileptics, includingepileptics who suffer from migraine, to prevent seizures.

[0008] The above discussed and other featues and attendant advantages ofthe present invention will become better understood by reference to thefollowing detailed description of the invention, and from the claims.

DETAILED DESCRIPTION

[0009] By treating migraine patients with the sulfamate compound offormula (I) or a pharmaceutically acceptable salt or derivative thereof,a substantial decrease in frequency of migrainous episodes can beachieved.

[0010] The administered compound is a sulfamate of the followingformula:

[0011] wherein

[0012] X is CH₂ or oxygen;

[0013] R₁ is hydrogen or lower (C₁-C₆) alkyl; and

[0014] R₂, R₃, R₄ and R₅ are independently hydrogen or lower alkyl and,when X is CH₂, R₄ and R₅ may be alkene groups joined to form a benzenering and, when X is oxygen, R₂ and R₃ and/or R₄ and R₅ together may be amethylenedioxy group of the following formula (II):

[0015]  wherein

[0016] R₆ and R₇ are the same or different and are hydrogen, lower alkylor are alkyl and are joined to form a cyclopentyl or cyclohexyl ring,

[0017] R₁ in particular is hydrogen or alkyl of about 1 to 4 carbons,such as methyl, ethyl and iso-propyl. Alkyl throughout thisspecification includes straight and branched chain alkyl. Alkyl groupsfor R₂, R₃, R_(4,) R₅, R₆, and R₇ are preferably of about 1 to 3 carbonsand include methyl, ethyl, iso-propyl and n-propyl. When X is CH₂, R₄and R₅ may combine to form a benzene ring fused to the 6-memberedX-containing ring, i.e., R₄ and R₅ are defined by the alkatrienyl group═CH—CH═CH—CH═.

[0018] In a particular group of compounds of formula (I), X is oxygenand both R₂ and R₃ and R₄ and R₅ together are methylenedioxy groups ofthe formula (II) wherein R₆ and R₇ are both hydrogen, both alkyl orcombine to form a spiro cyclopentyl or cyclohexyl ring, in particularwhere R₆ and R₇ are both alkyl such as methyl. A second group ofcompounds is that wherein X is CH₂ and R₄ and R₅ are joined to form abenzene ring. A third group of compounds of formula (I) is that whereinboth R₂ and R₃ are hydrogen.

[0019] Compounds of formula I which are preferred for use in the methodof the invention are tetrahydro-2H-pyran-2-yl)methane sulfamate,2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranose sulfamate, and2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranose methylsulfamate. Amost preferred compound is2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranose sulfamate, alsoknown as topiramate, having the chemical structure shown in formula III:

[0020] By pharmaceutically acceptable derivative is meant anypharmaceutically acceptable ester or salt of such ester of the compoundsof formula (I) or any other compounds which upon administration to therecipient is capable of providing (directly or indirectly) a compound offormula (I) or an anti-migraine active metabolite or residue thereof.

[0021] It will be appreciated by those skilled in the art that thecompounds of formula (I) may be modified to provide pharmaceuticallyacceptable derivatives thereof at any of the functional groups in thecompounds. Of particular interest are derivatives in which the sulfamateportion is masked by an imidate group that can be removed in aphysiological milieu to generate the parent drug, as disclosed in U.S.Pat. No. 5,258,402, and incorporated herein by reference. Suchderivatives are commonly known as prodrugs. Other derivatives ofinterest include sorbopyranose sulfamates (U.S. Pat. No. 5,384,327),fructopyranose cyclic sulfites and sulfates (U.S. Pat. No. 5,242,942),and phenylethyl sulfamates (U.S. Pat. No. 4,792,569), as well asacetazolamide (U.S. Pat. Nos. 2,554,816 and 2,980,679).

[0022] It will be appreciated by those skilled in the art that thepharmaceutically acceptable derivatives of the compounds of formula (I)may be derivatised at more than one position.

[0023] Pharmaceutically acceptable salts of the compounds of formula (I)include those derived from pharmaceutically acceptable, inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,toluene-p-sulphonic, tartaric, acetic, citric, formic, benzoic, malonic,napthalene-2-sulphonic and benzenesulphonic acids. Other acids such asoxalic acid, while not in themselves pharmaceutically acceptable, may beuseful in the preparation of salts useful as intermediates in obtainingcompounds useful in the method of the invention and theirpharmaceutically acceptable acid addition salts.

[0024] Salts derived from appropriate bases include alkali metal (e.g.sodium), alkaline earth metal (e.g. magnesium) ammonium and NR₄ (where Ris C₁₋₄ alkyl) salts.

[0025] Synthesis. The anti-migraine sulfamate derivatives employed inthe method of the invention can be synthesized according to the methodsdisclosed in U.S. Pat. No. 4,513,006, which is incorporated byreference. Other methods well known in the art for preparing thedisclosed sulfamate compounds, precursors, prodrugs, or derivativesthereof are also available, for example, those disclosed in U.S. Pat.Nos. 5,258,402, 5,384,327, 5,242,942, 4,792,569, 2,554,816 and2,980,679, all of which are incorporated by reference.

[0026] Pharmaceutical Compositions. Pharmaceutical compositions of theanti-migraine sulfamate derivatives of the invention can be preparedaccording to the methods disclosed in U.S. Pat. No. 4,513,006, which isincorporated by reference.

[0027] Treatment and Dosage. The amount of a compound of formula (I)useful for treatment of migraine in non-epileptic subjects will vary notonly with the particular compound selected but also with the route ofadministration, and the age and condtion of the patient treated. Ingeneral, suitable doses are in the range of from about ½ to 15 mg/kgbody weight per day, preferably in the range of 1 to 10 mg/kg day, mostpreferaby in the range of 1 to 5 mg/kg day. The method of the inventioncan conveniently administer daily dosages of compounds of formula (I) inunit dosages, for example, containing 50 to 400 mg, conveniently 100 to200 mg, of active ingredient per unit dosage form. Suitable treatment isgiven 1 or 2 times daily, depending upon clearance rate. Accordingly,the desired dose may be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day.

[0028] Treatment is preferably commenced before the onset of a migraineepisode and continued indefinitely.

[0029] While it is possible that, for use in the method of theinvention, compounds of formula (I) may be administered as the rawchemical, it is preferable to present the active ingredient as apharmaceutical formulation or composition which may further include apharmaceutically acceptable carrier. The carrier must be ‘acceptable’ inthe sense of being compatible with the other ingredients of theformulation and not deleterious to patient.

[0030] The following examples are intended to illustrate but not limitthe invention. While they are typical, other procedures known to thoseskilled in the art may alternatively be used to illustrate theembodiments and methods of the invention.

EXAMPLES Example 1 Anti-Migraine Activity in Epileptic Patients

[0031] The following example falls outside the scope of the appendedclaims.

[0032] Patient 1, an epileptic, suffered from complex partial seizuresand frequent episodes of migraine, some of which were temporally relatedto his seizures. Seizures and migraines were incompletely responsive tolarge doses of calcium channel blockers added to his anti-epileptic drugregimen. Patient 2 suffered from complex partial seizures and frequent,severe migraine episodes, requiring regular use of sumatripan.

[0033] Patient 1 took topiramate daily for 18 months. Patient 2 tooktopiramate daily for 10 months.

[0034] Patient 1 used 600 mg/d with substantial improvement inmigrainous episodes; his curent dosage is 800 mg/d. Patient 2 used 400mg/d with substantial improvement of her migraine headaches.

[0035] Except for one migrainous aura, Patient 1's migraine episodeswere nearly completely controlled and all calcium channel blockers wereable to be withdrawn. Patient 1 did not experience any adverse effectsfrom topiramate. Patient 2 had several episodes of basilar migrainewithout headache in the fifth and sixth months of toprimate use duringbrief cessation of her propanolol therapy, but was migraine-freethereafter until the tenth month, when she experienced 2 nocturnalgeneralized tonic clonic seizures, and subsequently died.

[0036] After taking 800 mg/d of topiramate, Patient 1 had notexperienced any migrainous episodes. Verapamil, nimodipine, andcimetidine (given to increase verapamil levels) were successfullywithdrawn. Patient 2 experienced substantially less frequent migraineheadaches after taking topiramate 200 mg/d, eliminating the average useof 2 administrations of sumatriptan per week once she was taking 300mg/d of topiramate.

Example 2 Anti-Migraine Activity in Non-Eplieptic Patients

[0037] To prevent migraine in non-epileptic patients, an effectiveamount of a pharmaceutical composition containing a sulfamate of formula(I), in particular 2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranosesulfamate (topiramate) is orally administered daily to the patient. Thedaily dosage is in the range of about 50 mg to 1000 mg for an averageadult human.

What is claimed is:
 1. A method of treating or preventing migraine in anon-epileptic human patient, said method comprising administering to thepatient an effective amount of a sulfamate of the following formula (I):

wherein X is oxygen; R₁ is hydrogen or lower alkyl; and R₂, R₃, R₄ andR₅ are independently hydrogen or lower alkyl and R₂ and R₃ and/or R₄ andR₅ together may be a group of the following formula (II):

 wherein R₆ and R₇ are the same or different and are hydrogen, loweralkyl or are alkyl and are joined to form a cyclopentyl or cyclohexylring.
 2. The method of claim 1 wherein R₂ and R₃, and R₄ and R₅,together are groups of the formula (II).
 3. The method of claim 1,wherein R₁ is alkyl of about 1 to 4 carbons; said lower alkyl group forR₂, R₃, R₄ and R₅ is alkyl of about 1 to 3 carbons; and said lower alkylfor R₆ and R₇ is alkyl of about 1 to 3 carbons.
 4. The method of claim1, wherein said sulfamate of formula (I) is selected from the groupconsisting of: (tetrahydro-2H-pyran-2-yl)methane sulfamate;2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranose sulfamate; and2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranose methylsulfamate.5. The method of claim 4, wherein said sulfamate is2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranose sulfamate.
 6. Themethod of claim 4 wherein the sulfamate is2,3:4,5-bis-O-(1-methylethyldiene)-β-D-fructopyranose methylsulfamate.7. The method of claim 1 wherein said pharmaceutical composition furthercomprises a pharmaceutically acceptable carrier.
 8. The method of claim1 wherein said sulfamate is present in a unit dosage amount of about 50to 400 milligrams.
 9. The method of claim 1 wherein the two oxygen atomsof the group of formula (II) are attached on the same side of thesix-membered ring depicted in formula (I).
 10. The method of claim 1wherein the sulfamate of formula (I) is a fructopyranose.
 11. The methodof claim 1 wherein in formula (I), R₁ is hydrogen.
 12. The method ofclaim 1 wherein the derivative is selected from the group consisting ofimidates (prodrugs), sorbopyranose sulfamates, fructopyranose cyclicsulfites and sulfates, phenylethyl sulfamates, acetazolamide, andmethazolamide.